Pdtm-36. Functional Genomic Analysis of Myc-amplified Medulloblastoma Nominates the Tgfb Pathway as a Clinically Viable Target
Year: 2017
Type: conference-abstract
Abstract: Group 3, MYC-amplified medulloblastomas (MB) remain exceedingly difficult to treat despite maximum tolerable doses of chemotherapy and radiation. Additionally, strategies to directly target MYC are not readily available for clinical use in pediatrics. Thus, to identify novel genetic dependencies and potential therapeutic targets in MYC-amplified MB tumors, we screened MB cell lines using a high-throughput shRNA library of 102,000 unique hairpins targeting nearly all genes in the coding genome. As expected, we observed genes such as MYC and components of the PI3K and FOXO pathways as statistically significant genetic dependencies in MYC-amplified MB cells relative to >70 non-MB cancer cell lines. However, we also observed consistent and marked sensitivity to hairpins targeting genes in the TGFb pathway. Supporting these findings, a meta-analysis of multiple genomic profiling studies showed mutations and/or copy number variations in several components of the TGFb pathway in Group 3 MBs and we further confirmed the presence of activated TGFb/SMAD pathway in Group 3/MYC-amplified MB tumors. Treatment of MYC-amplified MB cells with the FDA-approved TGFb inhibitor, LY-2157299, resulted in marked inhibition of phospho-SMAD2/3 levels as well as inhibition of non-canonical targets of the TGFb pathway. Proliferation assays showed LY-2157299 preferentially inhibited growth in MYC-amplified MB cells compared to non-MYC-amplified MB lines. This growth inhibition was accompanied by loss of markers of epithelial to mesenchymal transition, a known proxy for infiltrative and metastatic phenotype. Lastly, mice harboring patient-derived orthotopic xenografts treated with LY-2157299 lived significantly longer relative to vehicle-treated mice with immunohistochemical confirmation of downregulated phospho-SMAD2 and increased cleaved caspase, in vivo. Thus, our functional genomic and pre-clinical validation studies nominate TGFb pathway inhibitors as a therapeutic strategy for patients with Group 3/MYC-amplified medulloblastomas.
Source: Neuro-Oncology
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2767623108